Functional and structural changes in the prefrontal cortex of alcohol-dependent subjects are presumable associated with alterations in the basic structural unit of information transmission: the synapse. This involves the neuronal elements of the synapse and the glial support essential for its homeostasis. Thus, alterations in the structure and function of synapses, and the glial environment, namely astrocytes, are to be expected in the prefrontal cortex of alcohol-dependent subjects. However, very little knowledge exists on changes in synaptic proteins involved in neurotransmitter release and changes in the glial support of the synapses following chronic alcoholism. Therefore, in the present project it is hypothesized that significant alterations in the distribution of the synaptic proteins synaptophysin, synaptotagmin, syntaxin, and SNAP-25 will be observed in the postmortem dorsolateral, orbitofrontal, and anterior cingulate prefrontal cortex (all showing functional alterations in alcohol-dependence) of alcohol-dependent human subjects as compared to controls. Parallel changes should occur in astrocytic markers associated with synapses. It is further proposed that in a rodent model of alcohol-dependence with periods of withdrawal and relapse the synaptic changes observed will be comparable with those present in human alcohol-dependent subjects. Furthermore, it is predicted that synaptic and glial alterations in the animal model will be reversed or greatly reduced by neuroprotective treatments to alcohol-dependent experimental rodents. The hypotheses above will be tested with the following specific aims: Specific aim 1: To examine the distribution of synaptic proteins and astroglial markers in the prefrontal cortex of a rat model of alcohol-dependence using controls and alcohol preferring rats divided into the following main groups: rats with induced alcohol-dependence, rats with induced alcohol dependence and a period of remission, rats with induced alcohol-dependence and a period of withdrawal before relapsing to alcohol, rats with long term consumption and a period of abstinence of two months, rats not treated with alcohol. Specific aim 2: to assess the protective effects of treatment with neurotrophic factors and antioxidants on the distribution of synaptic proteins and astrocytic markers in the animal model. This will be done measuring and comparing the changes of synaptic proteins in treated animals with alcohol dependence versus alcohol-dependent rodents without treatment. Specific aim 3: To examine the distribution and content of synaptic proteins and astroglial in three regions of the prefrontal cortex in alcohol-dependent subjects with remission, alcohol-dependent subjects without remission and non-psychiatric controls. Thus, this proposal aims to assess in animal models of alcohol-dependence the ability of therapeutic interventions in preserving normal synaptic function.